Chronic lung diseases share the common feature of epithelial repair defects that contribute to loss of tissue homeostasis and further deterioration of lung function. Goals of this proposal are to improve our ability regulate tissue stem cells in health and disease, and to develop strategies to enhance epithelial regeneration either through stimulation of resident cells in situ or through development of cell-based therapeutic strategies. We have recently developed and characterized mice in which stem-like cells within conducting airways are amplified through conditional expression of an N-terminally truncated stabilized form of the [unreadable]-catenin protein. Goals of this application are to develop a mouse model for reversible in vivo stabilization of the stem cell phenotype through conditional expression of ?N[unreadable]-catenin. This model will be used to reveal critical stages of epithelial cell differentiation in the developing and adult lung that are susceptible to the effects of stabilized [unreadable]-catenin. Aim 1 will establish mice allowing conditional regulation of stabilized [unreadable]-catenin within CCSP- expressing cells of the developing and adult lung. This model will be used to determine the reversibility of differentiation-arresting properties of stabilized [unreadable]-catenin in mouse bronchiolar epithelial cells. Aim 2 will determine whether the differentiation modulating effects of stabilized [unreadable]-catenin are limited to stem cells or can be more broadly applied to modulate the differentiation potential of other progenitor cell types (Clara cells). Results from this application will determine whether genetic interventions (and by extrapolation, pharmacologic interventions) aimed at stabilizing [unreadable]-catenin can be used as a tool for amplification of airway stem cells in vivo. These experiments are a necessary prerequisite for the further development of therapeutic interventions aimed at cell-based therapies targeted towards endogenous lung tissue stem cells. PUBLIC HEALTH RELEVANCE: Epithelial cells that line airways of the lung fulfill critical functions in health that are lost in the setting of lung disease. The underlying defect is the capacity of the epithelium to repair or to re-establish normal function. Research to be conducted in this proposal will focus on the development of new methods to repair the epithelium of airways following injury. Goals are to take advantage of signaling pathways that regulate the number of epithelial cells capable of repairing the airway epithelium. These studies will provide new information for the development of drugs capable of enhancing epithelial repair and restoration of lung function to patients with chronic lung disease.